12.6 Gated Ion Channels in Chapter 12 Biochemical Signaling

12.6 Gated Ion Channels

Certain cells in multicellular organisms are “excitable”: they can detect an external signal, convert it into an electrical signal (specifically, a change in plasma membrane potential), and pass it on. Changes in membrane potential are effected by gated ion channels. Excitable cells play central roles in nerve conduction, muscle contraction, hormone secretion, sensory processes, and learning and memory.

Ion Channels Underlie Rapid Electrical Signaling in Excitable Cells

The excitability of sensory cells, neurons, and myocytes depends on ion channels, signal transducers that provide a regulated path for the movement of inorganic ions such as ${Na}^{+}, K^{+}, {Ca}^{2 +}$ $Na Superscript plus Baseline comma upper K Superscript plus Baseline comma Ca Superscript 2 plus$ , and ${Cl}^{-}$ $Cl Superscript minus$ across the plasma membrane in response to various stimuli. Recall from Chapter 11 that these ion channels are gated: they may be open or closed, depending on whether the associated receptor has been activated by the binding of its specific ligand (a neurotransmitter, for example) or by a change in the transmembrane electrical potential (voltage-gated ion channels). The ${Na}^{+} K^{+}$ $Na Superscript plus Baseline upper K Superscript plus$ ATPase is electrogenic; it creates a charge imbalance across the plasma membrane by carrying 3 ${Na}^{+}$ $Na Superscript plus$ out of the cell for every 2 $K^{+}$ $upper K Superscript plus$ carried in (Fig. 12-32a). The action of the ${Na}^{+} K^{+}$ $Na Superscript plus Baseline upper K Superscript plus$ ATPase makes the inside of the cell negative relative to the outside. Inside the cell, ${[K}^{+}]$ $left-bracket upper K Superscript plus Baseline right-bracket$ is much higher and ${[Na}^{+}]$ $left-bracket Na Superscript plus Baseline right-bracket$ is much lower than outside the cell (Fig. 12-32b). The direction of spontaneous ion flow across a polarized membrane is dictated by the electrochemical potential of that ion across the membrane, which has two components: the difference in concentration of the ion on the two sides of the membrane, and the difference in electrical potential $(V_{m})$ $left-parenthesis upper V Subscript m Baseline right-parenthesis$ , typically expressed in millivolts (see Eqn 11-4, p. 392). Given the ion concentration differences and a $V_{m}$ $upper V Subscript m$ of about $- 60 mV$ $negative 60 mV$ (inside negative), opening of a ${Na}^{+}$ $Na Superscript plus$ or ${Ca}^{2 +}$ $Ca Superscript 2 plus$ channel will result in a spontaneous inward flow of ${Na}^{+}$ $Na Superscript plus$ or ${Ca}^{2 +}$ $Ca Superscript 2 plus$ (and depolarization), whereas opening of a $K^{+}$ $upper K Superscript plus$ channel will result in a spontaneous outward flow of $K^{+}$ $upper K Superscript plus$ (and hyperpolarization) (Fig. 12-32b). In this case, $K^{+}$ $upper K Superscript plus$ moves out of the cell against the electrical gradient, because the large concentration difference exerts a stronger effect than the $V_{m}$ $upper V Subscript m$ . For ${Cl}^{-}$ $Cl Superscript minus$ , the membrane potential predominates, so when a ${Cl}^{-}$ $Cl Superscript minus$ channel opens, ${Cl}^{-}$ $Cl Superscript minus$ flows outward.

A two-part figure shows how the N a plus K plus A T P ase produces a transmembrane electrical potential in part a and how this affects the spontaneous movement of ions in part b. — FIGURE 12-32 Transmembrane electrical potential. (a) The electrogenic ${Na}^{+} K^{+}$ $Na Superscript plus Baseline upper K Superscript plus$ ATPase produces a transmembrane electrical potential of about −60 mV (inside negative). (b) Blue arrows show the direction in which ions tend to move spontaneously across the plasma membrane in an animal cell, driven by the combination of chemical and electrical gradients. The chemical gradient drives ${Na}^{+}$ $Na Superscript plus$ and ${Ca}^{2 +}$ $Ca Superscript 2 plus$ inward (producing depolarization) and $K^{+}$ $upper K Superscript plus$ outward, against its electrical gradient (producing hyperpolarization). The electrical gradient drives ${Cl}^{-}$ $Cl Superscript minus$ outward, against its concentration gradient (producing depolarization).

FIGURE 12-32 Transmembrane electrical potential. (a) The electrogenic ${Na}^{+} K^{+}$ $Na Superscript plus Baseline upper K Superscript plus$ ATPase produces a transmembrane electrical potential of about −60 mV (inside negative). (b) Blue arrows show the direction in which ions tend to move spontaneously across the plasma membrane in an animal cell, driven by the combination of chemical and electrical gradients. The chemical gradient drives ${Na}^{+}$ $Na Superscript plus$ and ${Ca}^{2 +}$ $Ca Superscript 2 plus$ inward (producing depolarization) and $K^{+}$ $upper K Superscript plus$ outward, against its electrical gradient (producing hyperpolarization). The electrical gradient drives ${Cl}^{-}$ $Cl Superscript minus$ outward, against its concentration gradient (producing depolarization).

A circular piece of plasma membrane is shown with plus signs around its outer boundary outside of the cell and minus signs lining its inner boundary. A light red rectangle labeled N a plus K plus A T Pase runs across the membrane at the top center and has a channel that runs vertically down to the midpoint and then angles to open into the cell at the lower left of the rectangle. Three purple strands connect the lower left of the rectangle to the upper left corner of a light blue triangle. A yellow diamond overlaps the lower right side of the light red rectangle and has a green rectangle against its lower right side. Arrows show that 2 green spheres labeled K plus have traveled through the channel in the light red rectangle into the cell and three red spheres labeled N a plus have traveled in the opposite direction to leave the cell. An orange oval labeled A T P has a curved arrow that runs through the yellow diamond and green rectangle to a gray oval labeled A D P accompanied by P subscript i. Text above the membrane reds, membrane potential equals negative 50 to negative 70 m V. Additional text to the upper left reads, the electrogenic N a plus K plus A T Pase establishes the membrane potential. Part b shows four vertical channels across the bottom of the circular membrane. The left-hand channel is labeled [N a plus] high and has an arrow pointing through the channel to the word low inside the cell. The second channel is labeled [C a 2 plus] high and has an arrow pointing through the channel to the word low inside the cell. The third channel is labeled [K plus] low and has an arrow pointing from the word high inside the cell through the channel to the outside of the cell. The fourth channel is labeled [C l minus] high and has an arrow pointing from the word high inside the cell through the channel to the outside of the cell. Accompanying text reads, ions tend to move down their electrochemical gradient across the polarized membrane.

The number of ions that must flow to produce a physiologically significant change in the membrane potential is negligible relative to the concentrations of ${Na}^{+} , K^{+}$ $Na Superscript plus Baseline zero width space comma upper K Superscript plus$ , and ${Cl}^{-}$ $Cl Superscript minus$ in cells and extracellular fluid, so the ion fluxes that occur during signaling in excitable cells have essentially no effect on the concentrations of these ions. With ${Ca}^{2 +}$ $Ca Superscript 2 plus$ , the situation is different; because the intracellular ${[Ca}^{2 +}]$ $left-bracket Ca Superscript 2 plus Baseline right-bracket$ is generally very low $(~ 10^{- 7} M)$ $left-parenthesis tilde 10 Superscript negative 7 Baseline upper M right-parenthesis$ , inward flow of ${Ca}^{2 +}$ $Ca Superscript 2 plus$ can significantly alter the cytosolic ${[Ca}^{2 +}]$ $left-bracket Ca Superscript 2 plus Baseline right-bracket$ , allowing it to serve as a second messenger.

The membrane potential of a cell at a given time is the result of the types and numbers of ion channels open at that instant. The precisely timed opening and closing of ion channels and the resulting transient changes in membrane potential underlie the electrical signaling by which the nervous system stimulates the skeletal muscles to contract, the heart to beat, or secretory cells to release their contents. Moreover, many hormones exert their effects by altering the membrane potential of their target cells. These mechanisms are not limited to animals; ion channels play important roles in the responses of bacteria, protists, and plants to environmental signals.

To illustrate the action of ion channels in cell-to-cell signaling, we describe the mechanisms by which a neuron passes a signal along its length and across a synapse to the next neuron (or to a myocyte) in a cellular circuit, using acetylcholine as the neurotransmitter.

Voltage-Gated Ion Channels Produce Neuronal Action Potentials

Signaling in the nervous system is accomplished by networks of neurons, specialized cells that carry an electrical impulse (action potential) from one end of the cell (the cell body) through an elongated cytoplasmic extension (the axon), to the synapse with the next neuron. The electrical signal triggers release of the neurotransmitter acetylcholine into the synaptic cleft, carrying the signal to the next cell (neuron) in the circuit. Initially, the plasma membrane of the presynaptic neuron is polarized (inside negative) through the action of the electrogenic ${Na}^{+} K^{+}$ $Na Superscript plus Baseline upper K Superscript plus$ ATPase, which pumps out three ${Na}^{+}$ $Na Superscript plus$ for every two $K^{+}$ $upper K Superscript plus$ pumped in (Fig. 12-32). A rapid sequence of opening and closing of several types of ion channels (Fig. 12-33) produces a wave of depolarization (an action potential) that sweeps the neuron from the cell body to the end of an axon. First, opening of a voltage-gated ${Na}^{+}$ $Na Superscript plus$ channel allows ${Na}^{+}$ $Na Superscript plus$ entry, and the resulting local depolarization causes the adjacent ${Na}^{+}$ $Na Superscript plus$ channel to open, and so on (Fig. 12-33, step ). The directionality of movement of the action potential is ensured by the brief refractory period that follows the opening of each voltage-gated ${Na}^{+}$ $Na Superscript plus$ channel. A split second after the action potential passes a point in the axon, voltage-gated $K^{+}$ $upper K Superscript plus$ channels open (step ), allowing $K^{+}$ $upper K Superscript plus$ exit, which brings about repolarization of the membrane to make it ready for the next action potential (step ).

A figure shows the roles of voltage-gated and ligand-gated ion channels in the transmission of impulses at a synapse. — FIGURE 12-33 Role of voltage-gated and ligand-gated ion channels in neural transmission. The steps are described in the text. Stimulation of the presynaptic neuron (top) triggers a wave of depolarization (blue arrow) followed by repolarization (red arrow), producing an action potential that sweeps along the axon. At the synapse, depolarization opens ${Ca}^{2 +}$ $Ca Superscript 2 plus$ channels, and ${Ca}^{2 +}$ $Ca Superscript 2 plus$ entry triggers acetylcholine release into the synaptic cleft. Acetylcholine diffuses across the cleft, opening receptor channels, depolarizing the postsynaptic cell, and starting an action potential in the postsynaptic cell. Note that, for clarity, ${Na}^{+}$ $Na Superscript plus$ channels and $K^{+}$ $upper K Superscript plus$ channels are drawn on opposite sides of the axon, but both types are uniformly distributed in the axonal membrane. Also, positive and negative charges are shown only on the left, but as the wave of potential sweeps the axon, the membrane potential is the same at any given point along the axon.

A horizontal piece labeled axon of presynaptic neuron extends down to a rounded bottom above a blue region rounded on both sides labeled synaptic cleft that extends to a concave structure below labeled cell body of postsynaptic neuron. The upper left side of the axon has plus signs along the outside and minus signs along the inside. Below, there is a light red voltage-gated N a plus channel with an arrow pointing through it from N a plus outside to a plus sign inside under the number 1 next to a box labeled depolarization at the start of a blue downward arrow. There is a minus sign on the outside of the membrane below, then a second light red channel with an arrow pointing through it from N a plus outside to a plus sign inside within the blue downward arrow. There is a minus sign on the outside of the membrane below, then a purple voltage-gated C a 2 plus channel with an arrow pointing through it from C a 2 plus outside to the number 3 inside beneath the point of the blue arrow inside. Beneath, there is a plus outside the membrane and a minus inside, then a closed voltage-gated C a 2 plus channel as the membrane bends outward along the left side of the rounded bottom. Four plus signs along the outside align with four minus signs along the inside along the left side of the rounded bottom. Beginning near the top of the right side of the membrane, there is a red arrow pointing down containing plus signs running along two green voltage-gated K plus channels that are each shown with arrows from the red arrow containing plus signs to K plus outside of the membrane. Accompanying text reads, 2 next to a box labeled repolarization. Two additional voltage-gated K plus channels below are closed. In the rounded bottom of the axon of the presynaptic neuron, there are six spheres surrounded by membranes that each have six molecules inside. These are labeled secretory vesicles containing acetylcholine. Two additional vesicles have fused with the membrane below and are releasing their contents into the blue area labeled synaptic cleft. One of these fused vesicles is next to the number 4. Two acetylcholine receptor ion channels are shown as two bundles of five vertical green cylinders in the top of the cell body of the postsynaptic neuron. An arrow points from one of the vesicles fused with the membrane above to one of these channels. The other cylinder has two of the red molecules attached and an arrow runs through it from N a plus, C a 2 plus above to the left side of the cell body, where the structure narrows and where there are two open N a plus channels with arrows pointing through them to plus signs in a downward blue arrow below. In the membrane below, there are plus signs on the outside of the membrane and minus signs on the inside of the membrane. On the right side, there is a red arrow with two plus signs and an arrow pointing from the bottom plus sign through an open green channel to K plus outside. A close green channel is below, then a minus sign inside and plus sign outside, then another closed green channel, then a minus inside and plus sign outside. Text between the blue and red arrows reads, action potential.

When the wave of depolarization reaches the axon tip, voltage-gated ${Ca}^{2 +}$ $Ca Superscript 2 plus$ channels open, allowing ${Ca}^{2 +}$ $Ca Superscript 2 plus$ entry (step ). The resulting increase in internal ${[Ca}^{2 +}]$ $left-bracket Ca Superscript 2 plus Baseline right-bracket$ triggers exocytotic release of the neurotransmitter acetylcholine into the synaptic cleft (step ). Acetylcholine binds to a receptor on the postsynaptic neuron or myocyte, causing its ligand-gated ion channel to open (step ). Extracellular ${Na}^{+}$ $Na Superscript plus$ and ${Ca}^{2 +}$ $Ca Superscript 2 plus$ enter through this channel, depolarizing the postsynaptic cell. The electrical signal has thus passed to the cell body of the postsynaptic neuron and will move along its axon to a third neuron (or a myocyte) by this same sequence of events. We see, then, that gated ion channels convey signals in either of two ways: by changing the cytoplasmic concentration of an ion (such as ${Ca}^{2 +}$ $Ca Superscript 2 plus$ ), which then serves as an intracellular second messenger, or by changing $V_{m}$ $upper V Subscript m$ and affecting other membrane proteins that are sensitive to $V_{m}$ $upper V Subscript m$ . The passage of an electrical signal through one neuron and on to the next illustrates both types of mechanism.

Neurons Have Receptor Channels That Respond to Different Neurotransmitters

Animal cells, especially those of the nervous system, contain a variety of ion channels gated by ligands, voltage, or both. Receptors that are themselves ion channels are classified as ionotropic, to distinguish them from receptors that generate a second messenger (metabotropic receptors). Acetylcholine acts on an ionotropic receptor in the postsynaptic cell. The acetylcholine receptor is a cation channel. When occupied by acetylcholine, the receptor opens to the passage of cations $({Na}^{+}, K^{+}, and {Ca}^{2 +})$ $left-parenthesis Na Superscript plus Baseline comma upper K Superscript plus Baseline comma and Ca Superscript 2 plus Baseline right-parenthesis$ , triggering depolarization of the cell. The neurotransmitters serotonin, glutamate, and glycine all can act through ionotropic receptors that are structurally related to the acetylcholine receptor. Serotonin and glutamate trigger the opening of cation $({Na}^{+}, K^{+}, {Ca}^{2 +})$ $left-parenthesis Na Superscript plus Baseline comma upper K Superscript plus Baseline comma Ca Superscript 2 plus Baseline right-parenthesis$ channels, whereas glycine opens ${Cl}^{-}$ $Cl Superscript minus$ -specific channels.

Depending on which ion passes through a channel, binding of the ligand (neurotransmitter) for that channel results in either depolarization or hyperpolarization of the target cell. A single neuron normally receives input from many other neurons, each releasing its own characteristic neurotransmitter with its characteristic depolarizing or hyperpolarizing effect. The target cell’s $V_{m}$ $upper V Subscript m$ therefore reflects the integrated input (see Fig. 12-1f) from multiple neurons. The cell responds with an action potential only if the integrated input adds up to a net depolarization of sufficient magnitude.

The receptor channels for acetylcholine, glycine, glutamate, and γ-aminobutyric acid (GABA) are gated by extracellular ligands. Intracellular second messengers — such as cAMP, cGMP, ${IP}_{3}$ $IP Subscript 3$ , ${Ca}^{2 +}$ $Ca Superscript 2 plus$ , and ATP — regulate ion channels of the type we saw in the sensory transductions of vision, olfaction, and gustation.

Toxins Target Ion Channels

Many of the most potent toxins found in nature act on ion channels. For example, dendrotoxin (from the black mamba snake) blocks the action of voltage-gated $K^{+}$ $upper K Superscript plus$ channels, tetrodotoxin (produced by puffer fish) acts on voltage-gated ${Na}^{+}$ $Na Superscript plus$ channels, and cobrotoxin (from cobras) disables acetylcholine receptor ion channels. Why, in the course of evolution, have ion channels become the preferred target of toxins, rather than some critical metabolic target such as an enzyme essential in energy metabolism?

Ion channels are extraordinary amplifiers; opening of a single channel can allow the flow of 10 million ions per second. Consequently, relatively few molecules of an ion-channel protein are needed per neuron for signaling functions. This means that a relatively small number of toxin molecules with high affinity for ion channels, acting from outside the cell, can have a pronounced effect on neurosignaling throughout the body. A comparable effect by way of a metabolic enzyme, typically present in cells at much higher concentrations than ion channels, would require far greater numbers of the toxin molecule.

SUMMARY 12.6 Gated Ion Channels

Ion channels gated by membrane potential or ligands are central to signaling in neurons and other cells.
The voltage-gated ${Na}^{+}$ $Na Superscript plus$ and $K^{+}$ $upper K Superscript plus$ channels of neuronal membranes carry the action potential along the axon as a wave of depolarization ( ${Na}^{+}$ $Na Superscript plus$ influx) followed by repolarization ( $K^{+}$ $upper K Superscript plus$ efflux). Arrival of an action potential at the distal end of a presynaptic neuron triggers neurotransmitter release.
The neurotransmitter (acetylcholine, for example) diffuses to the postsynaptic neuron (or the myocyte, at a neuromuscular junction), binds to specific receptors in the plasma membrane, and triggers a change in $V_{m}$ $upper V Subscript m$ . The cell body of the neuron has receptors for a variety of neurotransmitters or extracellular signals. The neuron’s $V_{m}$ $upper V Subscript m$ is the sum of the effects of all ion-channel contributions.
Neurotoxins, produced by many organisms, attack neuronal ion channels and are therefore fast-acting and deadly.